The Destiny Breast 11 trial compared a new drug to a chemotherapy regimen (ACTHP) that many US oncologists no longer use. This choice of a less common control arm makes it difficult for them to directly compare the new treatment's efficacy against their own current standard (TCHP), complicating adoption.

The NCI working group concluded that neither metastasis-directed therapy (MDT) nor systemic hormonal therapy should be required as a control arm in trials for biochemically recurrent (BCR) prostate cancer. This facilitates testing novel non-hormonal agents and reflects that surveillance is often a reasonable standard of care.

The PRESTO trial evaluated adding apalutamide (APA) and abiraterone (Abby) to a standard LHRH analog. The triplet combination arm demonstrated increased toxicity without any additional efficacy gains compared to the doublet arm (LHRH + APA). This finding reinforces that more intensive combination therapy is not always better and can be detrimental in this setting.

The EMBARK trial showed that enzalutamide monotherapy was superior to standard ADT monotherapy for metastasis-free survival. This suggests potent AR antagonism may be a more effective strategy than simply depleting the testosterone ligand, challenging the long-held dogma of ADT being the fundamental building block for systemic prostate cancer therapy.

The control arm in the EMBARK study was blinded to PSA results, preventing physicians from intervening with standard-of-care AR antagonists at PSA progression. This design likely delayed subsequent effective therapies, making the control arm underperform and potentially exaggerating the overall survival benefit of the experimental arms.

Pirtobrutinib's registrational trials used control arms (ibrutinib, bendamustine-rituximab) that are no longer the standard of care in the US. This strategy reflects the long timeline of trial design and the need to use comparators that are still considered a standard globally, ensuring broader regulatory acceptance and allowing for cross-trial comparisons.

Even when testing drugs in heavily pre-treated patients, clinical trials incorporate subtle biological selection criteria. For instance, the COMPASS trial excludes patients with visceral metastases, a tactic to enrich for a population more likely to respond and avoid the most aggressive disease subtypes.

The BRCA-Way trial showed a combination of abiraterone and olaparib was effective. However, its relevance is limited as many patients now receive abiraterone upfront. The next-generation TALENT trial is designed specifically to address this, testing if re-challenging with an AR-pathway inhibitor alongside a PARP inhibitor is beneficial, demonstrating how trial design must constantly evolve to answer questions raised by new standards of care.

The IMbark trial demonstrated that an ARPI (enzalutamide), either alone or with ADT, outperformed ADT monotherapy in high-risk patients. This pivotal finding raises the question of whether giving ADT alone in any setting, such as with radiation for localized disease, is now an outdated and inferior approach.